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Reuben J. Shaw

 

Reuben J. Shaw

Reuben J. Shaw

Hearst Endowment Assistant Professor
Molecular and Cell Biology Laboratory

"When a normal cell runs low on energy, it won't divide, but in some cases, cancer cells can override the built-in shutoff. The same cellular brake helps cells and organisms adapt their glucose metabolism. I am particularly interested in understanding the molecular link between cancer and metabolism since it embodies a critical intervention point for future therapeutics."

All cells need to coordinate their growth with the availability of nutrients. When the information flow breaks down, cells facing starvation simply continue to divide, spending energy currency like a frenzied credit card shopper—until the cellular cash runs out and cells die. Previously, Shaw and others had shown that AMPK, which acts like a gas gauge that lets the cell know when it is running on empty, takes its orders from a biochemical big boss, the protein LKB1. LKB1 is a so-called tumor-suppressor, whose loss causes the formation of benign growths, called hamartomas, and some types of malignant lung and colon cancer. If LKB dispatched AMPK—a metabolic master switch—to keep cell growth under control, then there had to be components of the pathway regulating cell growth that no one had discovered yet.

Shaw and his colleagues found that when cells are kept hungry in a culture dish, AMPK jumps into action and attaches a chemical phosphate group to a target protein named raptor. As a result, raptor, whose job is to cradle a growth-promoting protein called mTOR, is disabled, inactivating mTOR and halting cell division. Cells then safely switch into energy conservation mode until plentiful times return. Strikingly, the site of regulation on raptor looks similar from slime molds to humans, providing stunning insight into Mother Nature's reluctance to tinker with strategies that meet organisms' most basic needs: to know whether there is enough food around to grow.

Shaw's work hints at an even more profound clinical association: The widely used type 2 diabetes drug metformin activates AMPK, suggesting that the LKB1/ AMPK pathway is a molecular link between diabetes and cancer. This circuit could in part explain the increased cancer risk seen in type 2 diabetic patients, who are predisposed to breast, prostate, or colon cancer. Shaw's findings also predict that type 2 diabetics taking metformin may have a lowered risk of developing cancer, which has recently been borne out in two epidemiological studies. In addition, Shaw's lab recently collaborated with the Evans lab at Salk to show that AICAR, another drug that activates AMPK, promotes endurance, while directly suppressing cancer and type 2 diabetes.

Lab Photo

Left to right:
Front Row: Dana Gwinn, Dan Egan, Annabelle Merv, Debbie Vasquez, Reuben Shaw Back Row: Maria Mihaylova, David Shackelford, Jonathon Goodwin, Rebecca Kohnz

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Reuben J. Shaw

Faculty

Reuben J. Shaw

Reuben J. Shaw

Hearst Endowment Assistant Professor
Molecular and Cell Biology Laboratory

Reuben Shaw, assistant professor in the Molecular and Cell Biology Laboratory and the Dulbecco Laboratory for Cancer Research, studies signal transduction pathways that underlie the development of cancer as well as type 2 diabetes.

Our work centers around a human tumor suppressor named LKB1. LKB1 is mutationally inactivated in the familial cancer disease Peutz-Jegher Syndrome as well as in large percentage of sporadic lung adenocarcinomas. Interestingly, LKB1 encodes a threonine kinase that serves to activate a number of downstream kinases, including the AMP-activated protein kinase (AMPK), which is a critical regulator of metabolism, and the par-1/MARK family of kinases that regulate cell polarity.

Using a combination of proteomic and bioinformatics approaches, we identified AMPK as a direct substrate of LKB1. AMPK is a well known highly conserved regulator of cell metabolism that is activated under conditions of energy stress. We propose that the LKB1-dependent activation of AMPK in response to these stress stimuli may act as a low energy checkpoint in the cell. This unexpected connection between a well-known regulator of cellular metabolism and a tumor suppressor gene led to two immediate questions: Does AMPK have a role in tumor suppression and conversely, does the LKB1 tumor suppressor have a role in metabolic control in critical tissues in mammals? We have found that indeed both are true and that through the phosphorylation of specific targets by AMPK, these wide effects on physiology are regulated.

One way that LKB1 and AMPK regulate tumorigenesis is through regulation of the mTOR kinase, a conserved integrator of nutrient and growth factor signaling. We found that AMPK directly phosphorylates the TSC2 tumor suppressor and activates it to inhibit mTOR signaling. Consistent with this observation from cell culture, tumors lacking LKB1 were found to contain elevated levels of mTOR compared to surrounding epithelium. These findings culminated in the observation that three different human hamartoma syndromes, involving loss of TSC1/2, PTEN, and LKB1, all share a common biochemical underpinning: hyperactivation of mTOR signaling. We also generated a tissue-specific knockout of LKB1 in liver and also observed dramatic elevations of mTOR signaling in this context.

We chose to knockout LKB1 in liver as liver is known to be a tissue where AMPK activity is thought to be critical. Indeed, we found that loss of LKB1 led to a complete loss of AMPK activation and severe diabetes-like phenotypes in in these mice. We found that both gluconeogenic and lipogenic gene expression were upregulated in the livers of these mice, due in part to the loss of phosphorylation of a critical transcriptional coactivator termed TORC2 by AMPK and related kinases in the absence of LKB1. Finally we showed that metformin, one of the most-widely prescribed type-2 diabetes therapeutics in the world, requires LKB1/AMPK signaling in the liver in order to exert its therapeutic benefit.

Future studies in our lab will focus on further elucidating these critical signaling pathways at this emerging interface between cancer and diabetes. We will employ a variety of biochemical, cell-biological, and genetic mouse models to dissect these biological processes. In addition, we will examine how existing diabetic therapeutics may be useful in the treatment of tumors with defined genetic lesions.

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